tbuckley/cabot-search huggingface dataset:
Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits
Authors: Bo Yuan, Katharina V. Schulze, Nurit Assia Batzir, Jefferson Sinson, Hongzheng Dai, Wenmiao Zhu, Francia Bocanegra, Chin-To Fong, Jimmy Holder, Joanne Nguyen, Christian P. Schaaf, Yaping Yang, Weimin Bi, Christine Eng, Chad Shaw, James R. Lupski, Pengfei Liu
Journal: Genome Medicine (2022)

In medical genetics, discovery and characterization of disease trait contributory genes and alleles depends on genetic reasoning, study design, and patient ascertainment; we suggest a segmental haploid genetics approach to enhance gene discovery and molecular diagnostics. We constructed a genome-wide map for nonallelic homologous recombination (NAHR)-mediated recurrent genomic deletions and used this map to estimate population frequencies of NAHR deletions based on large-scale population cohorts and region-specific studies. We calculated recessive disease carrier burden using high-quality pathogenic or likely pathogenic variants from ClinVar and gnomAD. We developed a NIRD (NAHR deletion Impact to Recessive Disease) score for recessive disorders by quantifying the contribution of NAHR deletion to the overall allele load that enumerated all pairwise combinations of disease-causing alleles; we used a Punnett square approach based on an assumption of random mating. Literature mining was conducted to identify all reported patients with defects in a gene with a high NIRD score; meta-analysis was performed on these patients to estimate the representation of NAHR deletions in recessive traits from contemporary human genomics studies. Retrospective analyses of extant clinical exome sequencing (cES) were performed for novel rare recessive disease trait gene and allele discovery from individuals with NAHR deletions. We present novel genomic insights regarding the genome-wide impact of NAHR recurrent segmental variants on recessive disease burden; we demonstrate the utility of NAHR recurrent deletions to enhance discovery in the challenging context of autosomal recessive (AR) traits and biallelic variation. Computational results demonstrate new mutations mediated by NAHR, involving recurrent deletions at 30 genomic regions, likely drive recessive disease burden for over 74% of loci within these segmental deletions or at least 2% of loci genome-wide. Meta-analyses on 170 literature-reported patients implicate that NAHR deletions are depleted from the ascertained pool of AR trait alleles. Exome reanalysis of personal genomes from subjects harboring recurrent deletions uncovered new disease-contributing variants in genes including COX10, ERCC6, PRRT2, and OTUD7A. Our results demonstrate that genomic sequencing of personal genomes with NAHR deletions could dramatically improve allele and gene discovery and enhance clinical molecular diagnosis. Moreover, results suggest NAHR events could potentially enable human haploid genetic screens as an approach to experimental inquiry into disease biology.
Patients cut back on drugs to save on prescription fees as cost of living crisis bites
Authors: Gareth Iacobucci
Journal: BMJ (2022)

Since the outbreak of COVID-19 in China in December 2019, a pandemic has rapidly developed on a scale that has overwhelmed health services in a number of countries. COVID-19 has the potential to lead to severe hypoxia; this is usually the cause of death if it occurs. In a substantial number of patients, adequate arterial oxygenation cannot be achieved with supplementary oxygen therapy alone. To date, there has been no clear guideline endorsement of ward-based non-invasive pressure support (NIPS) for severely hypoxic patients who are deemed unlikely to benefit from invasive ventilation. We established a ward-based NIPS service for COVID-19 PCR-positive patients, with severe hypoxia, and in whom escalation to critical care for invasive ventilation was not deemed appropriate. A retrospective analysis of survival in these patients was undertaken. Twenty-eight patients were included. Ward-based NIPS for severe hypoxia was associated with a 50% survival in this cohort. This compares favourably with Intensive Care National Audit and Research Centre survival data following invasive ventilation in a less frail, less comorbid and younger population. These results suggest that ward-based NIPS should be considered as a treatment option in an integrated escalation strategy in all units managing respiratory failure secondary to COVID-19.
Cell proliferation and oncogene expression after bile duct ligation in the rat: Evidence of a specific growth effect on bile duct cells
Authors: Lorenzo Polimeno, Alessandro Azzarone, Qui Hua Zeng, Carmine Panella, Vladimir Subbotin, Brian Carr, Boumediene Bouzahzah, Antonio Francavilla, Thomas E. Starzl
Journal: Hepatology (1995)

The proliferative response of the rat liver was measured after temporary or permanent total biliary obstruction (BDO) and in different regions after selective ligation of the lobar ducts draining the right 60% of the hepatic mass. The results were compared with those after 70% partial hepatectomy (PH). Cell proliferation was assessed globally by measuring DNA synthesis and stratified to the separate cell populations with cytostaining techniques that allowed distinction of hepatocytes, duct cells, and nonparenchymal cells (NPCs). In selected experimental groups, gene expression was determined of transforming growth factor-β1 (TGFβ-1), prothrombin, c- erb -B2, transforming growth factor alpha (TGFα), human Cyclophilin (CyP), and 28S ribosomal RNA. The stimulation of a proliferative response to total BDO required obstruction for longer than 24 hours, but after this deligation did not switch off regeneration. In the first week after permanent BDO, there was progressive infiltration of NPCs, fibrous linkage of some portal areas, and a crescendo of DNA synthesis that was obvious at 24 hours, maximal at 48 hours, and back nearly to baseline at 6 days. At the 2-day mark, the bile duct cells had a 17-fold increase in proliferation, accompanied by a threefold to fourfold increase in hepatocyte renewal. Litle or no increase in expression of TGFα or the hepatocyte-specific prothrombin gene was detectable in the first 48 hours, whereas levels of the oncogene c- erb -B2 that is associated with cholangiocarcinoma were expressed from 48 to 96 hours. Livers subjected to regional BDO with or without immunosuppressive treatment with FK 506 and cyclosporine had an inflammatory reaction only on the side with ligated ducts. DNA synthesis increased in both the obstructed and freely draining lobes to approximately half the level that occurred after total BDO. The proliferation of the obstructed side was similar to the mixed duct cell/hepatocyte response after total BDO, but this almost exclusively involved duct cells on the freely draining side. In contrast to the findings after BDO, livers after PH regenerated maximally at 24 hours rather than 48 hours, had a predominantly noninflammatory hepatocyte as opposed to duct cell response, and had marked expression of the prothrombin and TGFα genes but only weakly and late of c- erb -B2 messenger RNA. The results show that the liver responds as a whole and in a biologically intelligent way to the nature of the injury inflicted on any part of it. It further implies the presence of humoral communications and control networks that assure organ homeostasis and relate this to total body homeostasis. (Hepatology 1995; 21:1070-1078.)
An American Text-Book of Gynecology, Medical and Surgical, for Practitioners and Students.
Journal: JAMA (1894)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Text-Book on Materia Medica, Therapeutics and Pharmacology.
Journal: JAMA (1900)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Gene transfer experiment in humans meets with scant approval
Authors: Roger S. Johnson
Journal: JAMA (1980)

When Martin J. Cline, MD, of the UCLA School of Medicine announced his recent trial of gene transfer in humans outside the United States, some thought it might be the opening of a new era in the treatment of genetic diseases. But this first attempt to use genetic engineering methods to treat patients directly has aroused the criticism of the community of scientists who are most involved in recombinant DNA research. Although most of the critics say they hope that therapy of this kind will eventually work, they believe that this attempt had no reasonable probability of success. Both clinicians and basic scientists in the fields of recombinant DNA research and hematology are concerned that Cline was brash and used poor scientific judgment in attempting such an experiment at this time. In the meantime, Cline has resigned as chief of the Division of Hematology-Oncology at the medical school while UCLA's
Cardiac Effects of a Cocktail
Authors: Lawrence Gould
Journal: JAMA (1971)

The hemodynamic effects of a cocktail in cardiac disease have not been previously studied, to our knowledge. Ten patients with cardiac disease and four normals underwent cardiac catheterization. Hemodynamic measurements were obtained prior to and 30 minutes after oral ingestion of 2 oz of Canadian whiskey. With alcohol, all of the patients with cardiac disease demonstrated a fall in the cardiac index and stroke index. Alcohol produced in the normals an increase in these measurements. The cardiac rate, systemic blood pressure, and pulmonary artery pressure were essentially unchanged in both groups. Small amounts of alcohol can impair cardiac function in patients with cardiac disease.
The Family Practice Concept Debated
Authors: Maurice Ross
Journal: JAMA (1978)

<h3>To the Editor.—</h3> Recently the news media and medical press (238:217, 232-235, 1977) have been promoting family practice. As a pediatrician who entered private practice 30 years ago in a community that had been treated almost entirely by general practitioners, I wish to express some caution in regard to this trend. In the past 30 years medical care has greatly improved in the smaller communities as well as in the larger medical centers. I can look back on the medical facilities of our community 30 years ago and, with a feeling of satisfaction and pride, observe the tremendous progress made in the area hospitals, mental health programs, public health nursing, school health, and the various agencies promoting better health and medicine for our community. These changes were stimulated by the specialists who settled in our community, not by family practitioners. Medicine has become so complex that it is impossible for
Looking Under the Lamppost: The Search for New Cancer Targets in the Human Kinome
Authors: Mireia Sueca-Comes, Elena Cristina Rusu, Anna M. Grabowska, David O. Bates
Journal: Pharmacological Reviews (2022)

The number of cancer drugs is increasing as new chemical entities are developed to target molecules, often protein kinases, driving cancer progression. In 2009, Fedorov et al. identified that of the protein kinases in the human kinome, most of the focus has been on a small subset. They highlighted that many poorly investigated protein kinases were cancer drivers, but there was no relationship between publications and involvement in cancer development or progression. Since 2009, there has been a doubling in the number of publications, patents, and drugs targeting the kinome. To determine whether this was an expansion in knowledge of well-studied targets—searching in the light under the lamppost—or an explosion of investigations into previously poorly investigated targets, we searched the literature for publications on each kinase, updating Federov et al.’s assessment of the druggable kinome. The proportion of papers focusing on the 50 most-studied kinases had not changed, and the makeup of those 50 had barely changed. The majority of new drugs (80%) were against the same group of 50 kinases identified as targets 10 years ago, and the proportion of studies investigating previously poorly investigated kinases (<i>&lt;</i>1%) was unchanged. With three exceptions [p38 mitogenactivated protein kinase (p38a), AMP-activated protein kinase catalytic <i>α</i>-subunit 1,2, and B-Raf proto-oncogene (BRAF) serine/threonine kinase], <i>&gt;</i>95% of publications addressing kinases still focused on a relatively small proportion (<i>&lt;</i>50%) of the human kinome independently of their involvement as cancer drivers. There is, therefore, still extensive scope for discovery of therapeutics targeting different protein kinases in cancer and still a bias toward well-characterized targets over the innovative searchlight into the unknown. <h3>Significance Statement</h3> This study presents evidence that drug discovery efforts in cancer are still to some extent focused on a narrow group of well-studied kinases 10 years after the identification of multiple novel cancer targets in the human kinome. This suggests that there is still room for researchers in academia, industry, and the not-for-profit sector to develop new and diverse therapies targeting kinases for cancer.
Animal Behavior in Psychedelic Research
Authors: Anna U. Odland, Jesper L. Kristensen, Jesper T. Andreasen
Journal: Pharmacological Reviews (2022)

Psychedelic-assisted psychotherapy holds great promise in the treatment of mental health disorders. Research into 5-hydroxytryptamine 2A receptor (5-HT<sub>2A</sub>R) agonist psychedelic compounds has increased dramatically over the past two decades. In humans, these compounds produce drastic effects on consciousness, and their therapeutic potential relates to changes in the processing of emotional, social, and self-referential information. The use of animal behavior to study psychedelics is under debate, and this review provides a critical perspective on the translational value of animal behavior studies in psychedelic research. Acute activation of 5-HT<sub>2A</sub>Rs produces head twitches and unique discriminative cues, disrupts sensorimotor gating, and stimulates motor activity while inhibiting exploration in rodents. The acute treatment with psychedelics shows discrepant results in conventional rodent tests of depression-like behaviors but generally induces anxiolytic-like effects and inhibits repetitive behavior in rodents. Psychedelics impair waiting impulsivity but show discrepant effects in other tests of cognitive function. Tests of social interaction also show conflicting results. Effects on measures of time perception depend on the experimental schedule. Lasting or delayed effects of psychedelics in rodent tests related to different behavioral domains appear to be rather sensitive to changes in experimental protocols. Studying the effects of psychedelics on animal behaviors of relevance to effects on psychiatric symptoms in humans, assessing lasting effects, publishing negative findings, and relating behaviors in rodents and humans to other more translatable readouts, such as neuroplastic changes, will improve the translational value of animal behavioral studies in psychedelic research. <h3>SIGNIFICANCE STATEMENT</h3> Psychedelics like LSD and psilocybin have received immense interest as potential new treatments of psychiatric disorders. Psychedelics change high-order consciousness in humans, and there is debate about the use of animal behavior studies to investigate these compounds. This review provides an overview of the behavioral effects of 5-HT<sub>2A</sub>R agonist psychedelics in laboratory animals and discusses the translatability of the effects in animals to effects in humans. Possible ways to improve the utility of animal behavior in psychedelic research are discussed.
Opportunities for Nitric Oxide in Potentiating Cancer Immunotherapy
Authors: Jihoon Kim, Susan N. Thomas
Journal: Pharmacological Reviews (2022)

Despite nearly 30 years of development and recent highlights of nitric oxide (NO) donors and NO delivery systems in anticancer therapy, the limited understanding of exogenous NO's effects on the immune system has prevented their advancement into clinical use. In particular, the effects of exogenously delivered NO differing from that of endogenous NO has obscured how the potential and functions of NO in anticancer therapy may be estimated and exploited despite the accumulating evidence of NO's cancer therapy–potentiating effects on the immune system. After introducing their fundamentals and characteristics, this review discusses the current mechanistic understanding of NO donors and delivery systems in modulating the immunogenicity of cancer cells as well as the differentiation and functions of innate and adaptive immune cells. Lastly, the potential for the complex modulatory effects of NO with the immune system to be leveraged for therapeutic applications is discussed in the context of recent advancements in the implementation of NO delivery systems for anticancer immunotherapy applications. <h3>SIGNIFICANCE STATEMENT</h3> Despite a 30-year history and recent highlights of nitric oxide (NO) donors and delivery systems as anticancer therapeutics, their clinical translation has been limited. Increasing evidence of the complex interactions between NO and the immune system has revealed both the potential and hurdles in their clinical translation. This review summarizes the effects of exogenous NO on cancer and immune cells in vitro and elaborates these effects in the context of recent reports exploiting NO delivery systems in vivo in cancer therapy applications.
A tool for mapping microglial morphology, morphOMICs, reveals brain-region and sex-dependent phenotypes
Authors: Gloria Colombo, Ryan John A. Cubero, Lida Kanari, Alessandro Venturino, Rouven Schulz, Martina Scolamiero, Jens Agerberg, Hansruedi Mathys, Li-Huei Tsai, Wojciech Chachólski, Kathryn Hess, Sandra Siegert
Journal: Nature Neuroscience (2022)

Environmental cues influence the highly dynamic morphology of microglia. Strategies to characterize these changes usually involve user-selected morphometric features, which preclude the identification of a spectrum of context-dependent morphological phenotypes. Here we develop MorphOMICs, a topological data analysis approach, which enables semiautomatic mapping of microglial morphology into an atlas of cue-dependent phenotypes and overcomes feature-selection biases and biological variability. We extract spatially heterogeneous and sexually dimorphic morphological phenotypes for seven adult mouse brain regions. This sex-specific phenotype declines with maturation but increases over the disease trajectories in two neurodegeneration mouse models, with females showing a faster morphological shift in affected brain regions. Remarkably, microglia morphologies reflect an adaptation upon repeated exposure to ketamine anesthesia and do not recover to control morphologies. Finally, we demonstrate that both long primary processes and short terminal processes provide distinct insights to morphological phenotypes. MorphOMICs opens a new perspective to characterize microglial morphology.
Vaping is “unlikely to be risk free,” finds evidence review
Authors: Matthew Limb
Journal: BMJ (2022)

We previously reported that cannabidiol (CBD), one of the <i>Cannabis sativa</i>-derived cannabinoids, induced functional CD4<sup>+</sup>CD25<sup>+</sup>FOXP3<sup>+</sup> Tregs in response to low level stimulation of PMA/Io. CBD increased CD25<sup>+</sup>FOXP3<sup>+</sup> cells in CD4<sup>+</sup>, CD4<sup>+</sup>CD25<sup>+</sup>, and CD4<sup>+</sup>CD25<sup>−</sup> T cells, as well as in CD4<sup>+</sup> T cells derived from FOXP3-GFP mice. T cell stimulation conditions were suboptimal PMA/Io (4 nM/0.05 μM, S/o) and ultrasuboptimal PMA/Io (1 nM/0.0125 μM, Us/o). We also observed that CBD + Us/o increased IL-2, IL-10 and TGF-β1 immunomodulatory cytokines. Here, we measured the effect of CBD + Us/o or S/o on CD4<sup>+</sup> cells. Splenocytes were treated with CBD (1–10 μM) for 30 min plus S/o or Us/o activation and cultured for 1 day or 5 days. Immunofluorescence staining showed that CBD + Us/o treatment increased the percentage of CD4<sup>+</sup> cells while CBD + S/o treatment decreased the percentage of CD4<sup>+</sup>cells. CD4<sup>+</sup>CD25<sup>+</sup> expression by Us/o or S/o activation alone was also measured. CD25 expression in response to Us/o activation was lower than that by S/o activation in CD4<sup>+</sup> cells. This study will provide important information on the effect of CBD on CD4 cells under differential immunological activation state by PMA/Io.